US3681409A - 9{60 -fluoro-16-fluoromethyleneprednisolone-21-enanthate and process for the preparation thereof - Google Patents

9{60 -fluoro-16-fluoromethyleneprednisolone-21-enanthate and process for the preparation thereof Download PDF

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Publication number
US3681409A
US3681409A US9408A US3681409DA US3681409A US 3681409 A US3681409 A US 3681409A US 9408 A US9408 A US 9408A US 3681409D A US3681409D A US 3681409DA US 3681409 A US3681409 A US 3681409A
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United States
Prior art keywords
enanthate
fluoromethyleneprednisolone
fluoro
acid
compound
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Expired - Lifetime
Application number
US9408A
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English (en)
Inventor
Klaus Irmscher
Gerhard Cimbollek
Hans-Gunther Kraft
Jurgen Harting
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Merck Patent GmbH
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Merck Patent GmbH
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01R—ELECTRICALLY-CONDUCTIVE CONNECTIONS; STRUCTURAL ASSOCIATIONS OF A PLURALITY OF MUTUALLY-INSULATED ELECTRICAL CONNECTING ELEMENTS; COUPLING DEVICES; CURRENT COLLECTORS
    • H01R4/00—Electrically-conductive connections between two or more conductive members in direct contact, i.e. touching one another; Means for effecting or maintaining such contact; Electrically-conductive connections having two or more spaced connecting locations for conductors and using contact members penetrating insulation
    • H01R4/02—Soldered or welded connections
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01R—ELECTRICALLY-CONDUCTIVE CONNECTIONS; STRUCTURAL ASSOCIATIONS OF A PLURALITY OF MUTUALLY-INSULATED ELECTRICAL CONNECTING ELEMENTS; COUPLING DEVICES; CURRENT COLLECTORS
    • H01R9/00—Structural associations of a plurality of mutually-insulated electrical connecting elements, e.g. terminal strips or terminal blocks; Terminals or binding posts mounted upon a base or in a case; Bases therefor
    • H01R9/22—Bases, e.g. strip, block, panel
    • H01R9/28—Terminal boards

Definitions

  • This invention relates to a 2l-ester of a 9a-fluoro-l6- substituted-prednisolone, more particularly to the 21- enanthate of 9a-fiuoro-l6-fluoromethyleneprednisolone and to its topical use in the treatment of skin conditions responsive to steroidal anti-inflammatory therapy.
  • CHgORz it (LL/V wherein, inter alia, R can be OH, R can be lower alkanoyl, R can be H, and X and -Y can be halogen.
  • that patent discloses 9a-fluoro-l6- fluoromethylene-prednisolone 2l-acetate.
  • the patent discloses the above class of compounds has anti-inflammatory activity. However, it does not describe the specific compound of this invention nor its excellent anti-proliferative activity.
  • antiproliferative activity means the inhibition of mitosis of fibroblast-cells and/or epidermis-cells.
  • results of the inhibition of mitosis of the fibroblast is measured by the reduction of proliferative tissue in the granuloma test.
  • mousetail-test the decrease of the mitotic activity leads to a reduction of the epidermal thickness.
  • the compound of this invention is suitably employed as a therapeutic agent and preferably is applied topically, for example for the treatment of psoriasis and other inflammatory skin diseases of exsudative and proliferative character such as eczema vulgare, microbial eczema, dyshidrotic eczema, allergic contact dermatitis, congestive eczema in ulcus cruris, intertrigo, dermatitis toxica, seborrheic eczema, erythroderma desquamativum Leiner, seborrheic erythrodermia of the aged, endogenic eczema, neurodermatitis circumscripta, insect stings, dermatitis solaris (sunburn), first and second degree burns and cauterizations, dermatitis bullosa striata pratensis, lichen ruber planus, psoriasis vulgaris, erytheme posterosive, non-fungus bal
  • 9afluoro-l-fluoromethyleneprednisolone or a lower 21- ester thereof can be esterified or transesterified with enanthic acid or a reactive derivative thereof, e.g., its acid chloride, anhydride or a lower-alkyl ester thereof.
  • the reaction is suitably conducted in an inert organic solvent, e.g., benzene or toluene, optionally in the presence of an acidic catalyst, e.g., p-toluenesulfonic acid or boron trifluoride. It is advantageous to remove the water produced during the reaction by azeotropic distillation.
  • an inert organic solvent e.g., benzene or toluene
  • an acidic catalyst e.g., p-toluenesulfonic acid or boron trifluoride. It is advantageous to remove the water produced during the reaction by azeotropic distillation.
  • enanthic acid e.g., enanthic acid chloride, enanthic acid bromide, or enanthic acid anhydride
  • a base e.g., dilute sodium hydroxide solution, pyridine, or triethylamine, preferably a base which can simultaneously serve as the solvent.
  • an additional inert solvent e.g., benzene or toluene. The esterification is normally conducted at room temperature, but proceeds more quickly with heating.
  • fluoromethyleneprednisolone can be reacted with a large excess of a lower-alkyl ester of enanthic acid, e.g., methyl enanthate or ethyl enanthate, or 9a-flluoro-l6- fluoromethyleneprednisolone-2 l-acetate or other lower-alkanoic 2 l -ester of Qa-fluoro- 1 6- fluoromethyleneprednisolone can be reacted with a large excess of enanthic acid, in the presence of a suitable catalyst, to produce the compound of this invention.
  • a lower-alkyl ester of enanthic acid e.g., methyl enanthate or ethyl enanthate
  • the latter method is advantageous, because the 2l-acetate can be obtained by the 21-acetoxylation of 9a-fluoro- 1 1B, 1 7a-dihydroxy-l 6-fluoromethylene-l ,4- pregnadiene-Ii,20-dione in the conventional manner and this ester can be converted without saponification to the free 21-alcohol directly to the desired 21- enanthate (I).
  • the transesterification agent e.g., a lower ester of enanthic acid or enanthic acid itself, can be employed as the reaction solvent.
  • the reaction can also be conducted in the presence of an additional inert solvent.
  • the boiling point of the inert solvent is preferably higher than that of the alcohol of the enanthic acid ester employed or higher than acetic acid if the 2l-acetate ester is employed.
  • a solvent is employed which forms an azeotropically boiling mixture with this alcohol or with acetic acid so that the thus-produced lower-aliphatic alcohol or acetic acid formed during the transesterification is distilled off from the reaction mixture, thereby shifting the equilibrium in favor of the desired ester (1).
  • Particularly suitable solvents are the hydrocarbons, e.g., benzene, toluene and xylene.
  • Suitable catalysts for the transesterification are small amounts of bases or basicreacting salts, e.g., potassium enanthate, and acids, e.g., p-toluene-sulfonic acid.
  • bases or basicreacting salts e.g., potassium enanthate
  • acids e.g., p-toluene-sulfonic acid.
  • the compound of this invention can be employed as a mixture with solid, liquid and/or semi-liquid pharmaceutical excipients in the human or veterinary medicine.
  • Suitable carrier substances are organic or inorganic compounds which are suitable for parenteral, enteral, or preferably topical application, which do not react with (I), such as, for example, one or more of water, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, mineral oil,
  • solutions particularly suitable are solutions, preferably oily solutions, as well as suspensions or emulsions.
  • Suitable for enteral application are tablets, dragees, syrups, juices, and suppositories.
  • the compound of this invention can be formulated into solutions, suspensions and emulsions, e.g., salves, creams, lotions, tinctures, also aerosols, or powders.
  • auxiliary agents such as, for example, preservatives, stabilizers, wetting agents, salts for influencing osmotic pressure, buffers, colorings, flavorings, and/or aromatics.
  • the compound of this invention is administered orally preferabiy in a dosage of 0.3-6 mg., especially 1-3 mg, as a mixture with l-5,000 mg., preferably SO SOO mg., of the pharmaceutical carrier per dosage unit.
  • the content thereof in pharmaceutical preparations adapted for the topical application preferably is between 0.01 and 1 percent by weight, more preferably between 0.025 and 0.1 percent by weight.
  • mice in accordance with the method of JARRE'IT and SPEARMAN (Histochemistry of the Skin-Psoriasis, English Universities Press Ltd., London, 1964) male mice (mean body weight: 20-30 g) are treated with the test compounds daily for 10 days.
  • Various concentrations of the test compounds are suspended in peanut oil, applied to the tail and rubbed in mechanically from the root to the tip (volume applied: 0.1 nil/animal).
  • the controls are merely subjected to treatment with the suspension vehicle.
  • the animals are sacrificed on the day after the last application.
  • a segment from the central third of the tail is dissected and, after removal of the tail bones, fixed in Bouins solution for histological processing (consisting of formaldehyde solution, glacial acetic acid and a saturated solution of trinitrophenol), embedded in parafiin and cut into sections.
  • the histological sections are stained with hematoxylin-eosin.
  • the epidermal thickness is measured microscopically by means of a calibrated ocular micrometer, each histological section being examined in three different places.
  • the mean per animal is calculated from a total of 24 tail measurements and used for the determination of the mean of each experimental group.
  • EXAMPLE 1 12. l g. of 9a-fluorol6- fluoromethyleneprednisolone is dissolved in ml. of absolute pyridine, mixed with 4.85 g. of enanthic acid chloride, and allowed to stand at room temperature for 2 days. The reaction mixture is stirred into 2 1. of ice water; the precipitate is vacuum-filtered, washed with water, dried, and chromatographed on g. of silica gel with chloroform/acetone (9:1). The fractions containing the desired substance are combined, evaporated, and the residue recrystallized from ether, thus obtaining 9a-fluoro-lo-fluoromethyleneprednisolone-2 l -enanthate, m.p. 202204.
  • EXAMPLE 2 ten g. of 9a-fluorol 6-fluoromethyleneprednisolone- 2l-acetate is mixed with 40 ml. of enanthic acid and 1 g. of potassium enanthate. The mixture is gently heated at 12 mm, so that enanthic acid and thus-formed acetic acid distil over slowly. After 5 hours, the reaction mixture is cooled, the residue is taken up in chloroform, and washed successively with saturated Nl-hCl solution, NaHCO solution, and water.
  • the coating (150 mg.) is a mixture of corn starch, sugar, talc, and tragacanth.
  • EXAMPLE C Injection Solution A solution of 200 g. of v 9a-fluoro-l6- fluoromethylene-prednisolone-2l-enanthate in 99.8 kg. of sesame oil is prepared and filled into ampoules so that each ampoule contains 2 mg. of the above-mentioned active substance.
  • EXAMPLE H Lotion 9a-Fluoro-16-fluoromethyleneprednisolone-2 lenanthate 0.1% Paraffin oil (thickened) 10.0% Ethanol 2.0% Glycerin 1.0% Propylene glycol 2.0% Sorbic acid 0.15% Fatty alcohol polyglycol ether 2.0% Mixture of cetyl stearyl alcohol, sodium salt of cetylstearylsulfuric acid, and nonionic emulsifier 0.5% Perfume oil 0.01% Water 82.24%

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US9408A 1969-02-11 1970-02-06 9{60 -fluoro-16-fluoromethyleneprednisolone-21-enanthate and process for the preparation thereof Expired - Lifetime US3681409A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE1906586A DE1906586C3 (de) 1969-02-11 1969-02-11 9 alpha-Fluor-16-fluormethylenprednisolon-21-önanthat, Verfahren zu seiner Herstellung und diese enthaltende pharmazeutische Zubereitung

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US (1) US3681409A (enrdf_load_html_response)
AT (3) AT305503B (enrdf_load_html_response)
BE (1) BE745708A (enrdf_load_html_response)
BR (1) BR6915196D0 (enrdf_load_html_response)
CH (1) CH534673A (enrdf_load_html_response)
DE (1) DE1906586C3 (enrdf_load_html_response)
DK (1) DK123475B (enrdf_load_html_response)
ES (1) ES376409A1 (enrdf_load_html_response)
FR (1) FR2034535B1 (enrdf_load_html_response)
GB (1) GB1247641A (enrdf_load_html_response)
HU (1) HU165223B (enrdf_load_html_response)
IL (1) IL33812A (enrdf_load_html_response)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190083384A1 (en) * 2017-09-19 2019-03-21 Tci Co., Ltd. Method for conditioning skin by using earthworm protein

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU572589B2 (en) 1983-12-14 1988-05-12 Upjohn Company, The 11(alpha)-difluoromethyl and (e)-and (z)-11-fluoromethylene steroids

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB939510A (en) * 1959-02-10 1963-10-16 Ciba Ltd Process for the manufacture of pregnadienes
US3161661A (en) * 1961-06-08 1964-12-15 Merck Ag E 16-halomethylene steroids

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB939510A (en) * 1959-02-10 1963-10-16 Ciba Ltd Process for the manufacture of pregnadienes
US3161661A (en) * 1961-06-08 1964-12-15 Merck Ag E 16-halomethylene steroids

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190083384A1 (en) * 2017-09-19 2019-03-21 Tci Co., Ltd. Method for conditioning skin by using earthworm protein

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IL33812A (en) 1973-05-31
GB1247641A (en) 1971-09-29
DE1906586C3 (de) 1974-01-03
CH534673A (de) 1973-03-15
FR2034535B1 (enrdf_load_html_response) 1973-01-12
DE1906586B2 (de) 1973-06-07
ES376409A1 (es) 1973-01-01
AT303277B (de) 1972-10-15
DK123475B (da) 1972-06-26
NL7001197A (enrdf_load_html_response) 1970-08-13
IL33812A0 (en) 1970-03-22
DE1906586A1 (de) 1970-11-05
AT305503B (de) 1973-01-15
FR2034535A1 (enrdf_load_html_response) 1970-12-11
HU165223B (enrdf_load_html_response) 1974-07-27
BE745708A (enrdf_load_html_response) 1970-08-10
PL80839B1 (enrdf_load_html_response) 1975-08-30
AT298692B (de) 1972-05-25
SE356744B (enrdf_load_html_response) 1973-06-04
BR6915196D0 (pt) 1973-02-13

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